Millions of Americans are infected with one or more types of human papillomavirus (HPV). Many of the more than 100 HPV types are tropic for the genital organs and fall into two general classes: those causing cervical neoplasia; and those causing condylomata (genital warts). In children, unfortunate enough to acquire the condylomatous viral types from their mothers, the infection produces the commonest benign neoplasm of the larynx, recurrent respiratory papillomatosis (RRP). RRP causes voice disturbance which is associated with very significant morbidity and degrades quality of life. Human voice is one of the most unique and defining aspects of our species as it leads directly to our ability to engage in complex communications. Chronic voice disturbance prompts evaluation by an otolaryngologist, and uncontrolled disease may lead to death through airway occlusion. Despite the surgeon being able to diagnose and manage the papillomas, the lesions recur repeatedly since there is no known cure. Most patients must endure multiple surgeries. The disease may go into remission in some but hoarseness often persists for life. We state that there is a genetic susceptibility to RRP, and in this application we propose to determine the genetic basis for host susceptibility to HPV using RRP as a model, enabling rational therapy development. Ongoing collaborations between the RRP Task Force, 19 medical institutions, the Center for Genomic Sciences and two patient-support groups has yielded the broadest-based RRP DNA repository ever assembled. The repository will be grown to the size needed for the performance of genome-wide genetic association studies that are sufficiently powered to identify susceptibility genes. Susceptibility loci will be identified by comparing the patients to their parents as well as to controls and then performing Transmission Disequilibrium Testing and case-control genetic association analyses. Also a quantitative trait locus analysis will be performed in which genotype will be compared to the disease aggressiveness. To reduce expenses, a validated two step approach will be used. Complete genotyping of 300,000 SNPs/subject is only performed on a third of the sample and the balance of the samples are then genotyped only at the most promising loci identified from step 1. Further, high density genetic association studies will be performed for ~20 candidate genes that are known to play a role in HPV cell biology. Finally, all candidate genes identified by both a priori and a postori studies will be sequenced to identify those genetic lesions responsible for this life-changing disease.